Amino compounds having antispasmodic properties



United States Patent This invention relates to compounds of the general formula CH 0 (CH) N/ in which Y is hydrogen or a halogen, X is hydrogen, a lower alkyl group or a halogen, R1 is an alkyl group having from 1 to 6 carbon atoms, each R stands for an alkyl group having from 1 to 4 carbon atoms or the two Rs together stand for the group and n is 2 or 3. The compounds in which X or Y is iodine tend to be unstable. For this reason chlorine and bromine are the preferred halogens.

The compounds generally have antispasmodic properties and some of them have been found to possess this property to a sufiicient degree to be clinically useful.

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The compounds generally may be prepared by reacting the alkali metal salt of an amino alcohol of the formula in which R and n have the values noted above and M is an alkali metal, preferably sodium, with a compound of the general formula in which R1 X and Y have the values noted above and Hal is a halogen. The alkali metal salt of the amino alcohol may be prepared by refluxing a solution of the corresponding amino alcohol in a suitable solvent such as xylene in the presence of an excess of the alkali metal. The excess or unconsumed alkali metal is separated from the resulting solution and the halogen derivative of the alkoxy halogen benzyl compound is added and the mixture refluxed. The resulting amino ether is extracted from the xylene solution with dilute aqueous hydrochloric acid, precipitated by neutralizing the hydrochloric solution with sodium hydroxide and is then purified by distillation under reduced pressure.

The following specific example of the preparation of the compound 5 of the above table is illustrative.

A mixture of 11.7 grams of diethylaminoethanol, 4 grams of sodium and cc. of xylene is refluxed for 35 Specific examples of such compounds are the following: 5 hours and the resulting solution separated from excess Melting Point Number R1 R X Y n Boiling Point of of the the Amine Hydrochloride, degrees CHa 432115 -H H 2 1e0-170/5 mm 102-105 CH1 -C2H CH; --11 2 1e0-1e7/3 mm.-. 87-92 OH1 CzH5 01 H 2 165170/3 mm. -123 -CH3 CH3 Br -H 2 165170/5 mm 104-107 CH1 -01Hi Br H 2 1e0-170/5 mm... 115-117 0H5 C1H0 Br H 2 200-210 5 mm.-. 133-140 CH3 C;-H Br Br 2 1s5-195/3 mm". 124-127 02H5 -C;H5 -Br H 2 1s5-190/5 mm. 147-149 C3H1 C2H5 -Br -11 2 1s5-195/5 mm 134-137 OH2 CH=CH2 C2H5 -Br -11 2 l85190/3 mm -132 /OH; 11 .1 CH 01H5 -Br -H 2 l80190/3 mm.-- -142 12 -C4H0 o2H5 Br -H 2 190-200/5 mm.-. 104-107 (normal) 13 C5H 0,H1 Br -H 2 190200/5 mm... 80-82 (secondary) 14 0H1; O2H5 -Br H 2 210-220/5 (normal) /CH; 15 CH -C1HQ Br H 2 2l5-225/6 mm.. 62-70 CH2CHg 1e -03; 0 -Br H 2 -l95/5 mm-.- 162-167 -CH2-CH2 /CH; 17 CH2 -olm Br -H 3 -205/5 93-97 1s CH3 -C2H Cl 01 2 167175/3 mm 113-117 19 CH; -o,H Br Br 2 21o-225/3 mm..- 70-75 sodium. 28 grams of 2-methoxy-5-bromobenzyl bromide are then introduced into the solution and the resulting mixture is refluxed for 2 hours. The mixture is then filtered to separate sodium bromide. The filtrate is extracted with dilute aqueous hydrochloric acid solution, the resulting solution made alkaline by the addition of sodium hydroxide solution and then extracted with ethyl ether. The resulting ether solution is distilled first to remove the ether and then under vacuum to distill over the product. 26 grams of a product boiling within the range 190 C. to 200 C. at 5 mm. pressure is recovered. This product is dissolved in dry ether and dry HCl is passed through the ether solution "to form the hydrochloride. The hydrochloride after purification by crystallization twice from a mixture of methanol and other has a melting point of ll5-ll8 C.

All of the compounds are active antispasmodic agents when applied parenterally but so far as i have found only compounds 7, l3 and 19 are useful when applied by mouth. Their activity is demonstrated by their ability to inhibit gastrointestinal activity as measured by the advancement of an inert charcoal meal in a given period of time. The reduction in gastrointestinal activity is proportional to the dosage. Toxicity or lethal dosage has been found to be safely in excess of the useful dosage range. They have only a slight effect as compared with atropine on vagal transmission and the cervical sympathetics. The efiect on salivary flow .is negligible as compared with atropine. They produce a substantial but transitory fall of blood pressure which is not inhibited by atropine blockage or by nicotine, or by tetraethyl ammonium chloride. From these facts it appears that the depressor response is not dependent upon transmission through the autonomic innervations and that the locus of action is principally on the cell directly.

The compounds also generally show anaesthetic activity when administered parenterally, some of them being more powerful i. e. giving a greater anaesthetic efiect per unit of weight and a longer lasting anaesthetic efiect than formula in which X stands for a member of the group consisting of chlorine and bromine, Y stands for a member of the group consisting of chlorine and bromine, R1 is an alkyl group having from 1 to 6 carbon atoms, R and R stand tor a member of the group consisting of two alkyl groups each having 1 to 4 carbon atoms and the group and n is a member of the group consisting of 2 and 3.

2. A new product as defined in claim 1 in which both X and Y are bromine atoms.

3. A new product as defined in claim 1 in which X and Y are both bromine atoms, both Rs are ethyl groups, R1 is a methyl group and n is 2.

4. A new product as defined in claim 1 in which both X and Y are bromine atoms, both Rs are butyl groups, R is a methyl group and n is 2.

5. A new product as defined in claim 1 in which both X and Y are chlorine atoms, both Rs are ethyl groups, R1 is a methyl group and n is 2.

References Cited in the tile of this patent UNITED STATES PATENTS 2,397,799 Martin et al. Apr. 2, 1946 

1. AS A NEW PRODUCT A COMPOUND OF THE GENERAL 